Epigenetic and parasitological parameters are modulated in EBi3-/- mice infected with Schistosoma mansoni

Abstract

Schistosoma mansoni adaptive success is related to regulation of replication, transcription and translation inside and outside the intermediate and definitive host. We hypothesize that S. mansoni alters its epigenetic state in response to the mammalian host immune system, reprogramming gene expression and altering the number of eggs. In response, a change in the DNA methylation profile of hepatocytes could occurs, modulating the extent of hepatic granuloma. To investigate this hypothesis, we used the EBi3 -/murine (Mus musculus) model of S. mansoni infection and evaluated changes in new and maintenance DNA methylation profiles in the liver after 55 days of infection. We evaluated expression of epigenetic genes and genes linked to histone deubiquitination in male and female S. mansoni worms. Comparing TET expression with DNMT expression indicated that DNA demethylation exceeds methylation in knockout infected and uninfected mice and in wild-type infected and uninfected mice. S. mansoni infection provokes activation of demethylation in EBi3 -/-I mice (knockout infected). EBi3 -/-C (knockout uninfected) mice present intrinsically higher DNA methylation than WTC (control uninfected) mice. EBi3 -/-I mice show decreased hepatic damage considering volume and reduced number of granulomas compared to WTI mice; the absence of IL27 and IL35 pathways decreases the Th1 response resulting in minor liver damage. S. mansoni males and females recovered from EBi3 -/-

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

“…However, taken in the context of our recent findings that ES-62 can promote both health- and life-span in male mice undergoing obesity-accelerated ageing 6 , it is in line with helminths having evolved such an overarching inflammation-resolving and repair/regeneration strategy to counter the chronic inflammation and tissue pathology they would otherwise elicit. Consistent with this, it has recently been reported that another parasitic trematode, Schistosoma mansoni, induces hepatocyte DNA hypomethylation that is associated with reduced tissue pathology and granuloma formation in the acute phase of infection in mice 101 , supporting the idea that epigenetic changes induced by helminth infection appear to be indirectly important in promoting long-term helminth survival.…”

“…Interestingly, such epigenetic remodelling was impacted by the inflammatory context, which modulated the (reciprocal) epigenetic changes occurring in both the host hepatocytes and the worms to determine the levels of liver pathology 101 . The potential importance of the evolution of such complex host-worm epigenetic regulatory networks is highlighted by evidence that CD4 T cells, from children recently exposed to tuberculosis and infected with Schistosoma haematobium showed profound differential DNA methylation, relative to those from uninfected children, that was associated with Th2-skewing of tuberculosis (TB)-specific responses away from the protective Th1/IFN γ phenotype 102 .…”

Epigenetic markers associated with schistosomiasis

“…Epigenetic markers are produced through interactions between the parasite and the environment, as well as by interactions with host-specific immune responses. Therefore, to use epigenetic factors as biomarkers, the relationships between parasite and its definitive host must be considered ( Mota et al, 2020 ). In epigenetic processes where the interactions occur by modifying the epigenetic state, there is the participation of enzymes such as: DNA methyltransferases (DNMT), protein arginine methytransferase (PRMT), protein lysine methyltransferase (PKMT), lysine demethylases (KDM), protein lysine acetyltransferase, protein lysine deacetylase (HDAC), kinases, ubiquitin conjugating enzymes (E2), deubiquitinating enzymes (DUBs), and others, presented in Table 1 .…”

“…In S. haematobium for example the promoter of RASSF 1A and TIMP3 genes is hypermethylated and can be used as a biomarker of S. haematobium infection ( Zhong et al, 2013 ). Disturbance in the global content of 5-mC and in the expression of DNMTs and TETs (Ten eleven translocation) were detected in the liver of infected mice compared to uninfected maybe in the future some specific region or a set of expression profile could be used as schistosomiasis biomarker ( Mota et al, 2020 ).…”

“…Knowledge of the epigenetic signatures of S. mansoni and an understanding of the intriguing biological role of these molecules is fundamental for the clarification of regulatory processes, the immune response of the mammalian host, and the mechanisms of host and parasite interactions ( Cabezas-Cruz et al, 2014 ; Mota et al, 2020 ). It is possible to assume that patterns involving DNA methylation, histone modifications, and ncRNA can act as epigenetic biomarkers of schistosomiasis ( Berdasco et al, 2018 ).…”